Functionalized 2,3′-Bipyrroles and Pyrrolo[1,2-c]imidazoles from Acylethynylpyrroles and Tosylmethylisocyanide

An efficient method for the synthesis of pharmaceutically prospective but still rare functionalized 2,3′-bipyrroles (in up to 80% yield) by the cycloaddition of easily available acylethynylpyrroles with tosylmethylisocyanide (TosMIC) has been developed. The reaction proceeds under reflux (1 h) in the KOH/THF system. In the t-BuONa/THF system, TosMIC acts in two directions: along with 2,3′-bipyrroles, the unexpected formation of pyrrolo[1,2-c]imidazoles is also observed (products ratio~1:1).


Introduction
The widespread applications of pyrroles, including their assemblies and the functionalized fused derivatives, in such fields as pharmacology, medicinal chemistry and materials science as well as their significance as precursors in the synthesis of many natural products have made this class of compounds one of the most important in heterocyclic chemistry [1][2][3][4][5][6][7][8][9][10][11][12].
In the light of the foregoing, it is clear that the synthesis of new pyrrole derivatives as potential drugs or that of their precursors is an important synthetic challenge.
In this paper, we report on the methods for the synthesis of such important representatives of pyrrole assemblies and fused pyrroles as 2,3 ′ -bipyrroles and pyrrolo [1,2c]imidazoles via the reaction of 2-acylethynylpyrroles with tosylmethylisocyanide (TosMIC).
It is known that readily available 2,2 ′ -bipyrroles are widely used as key building blocks in the synthesis of pyrrole macrocycles with different pharmacological activities [16].Investigations of 2,3 ′ -bipyrroles are still restricted by the absence of suitable facile approaches to these unique molecules.Only a few preparative significant methods for the synthesis of these assemblies are known.Among them are 1,3-dipolar cycloaddition of unsymmetrical münchnones and nitrovinylheterocycles in the presence of N,N ′ -diisopropylcarbodiimide (DIPC) (Scheme 1a) [17] and cycloaddition of acylethynylpyrroles with diethyl aminomalonate hydrochloride (Scheme 1b) [18].
Compounds of this class are antagonists of the 5-HT3 receptor with antiemetic activity especially effective in chemotherapy [23], the neuropeptide S receptor associated with biological processes such as appetite and food intake, movement, wakefulness, activation and anxiety [24], and the TNF receptor widely employed for the treatment of rheumatoid arthritis [25].Pyrrolo [1,2-c]imidazoles also exhibit anticancer [26,27], antioxidant, antibacterial [28], anti-inflammatory and neuroprotective [29] activities.
Compounds of this class are antagonists of the 5-HT3 receptor with antiemetic activity especially effective in chemotherapy [23], the neuropeptide S receptor associated with biological processes such as appetite and food intake, movement, wakefulness, activation and anxiety [24], and the TNF receptor widely employed for the treatment of rheumatoid arthritis [25].Pyrrolo [1,2-c]imidazoles also exhibit anticancer [26,27], antioxidant, antibacterial [28], anti-inflammatory and neuroprotective [29] activities.
Despite the insufficient knowledge of the biological activity of 2,3 ′ -bipyrroles, there is information about the prospects of their use as anticancer drugs [30,31] and EGFR inhibitor [32] (Figure 1).
Compounds of this class are antagonists of the 5-HT3 receptor with antiemetic activity especially effective in chemotherapy [23], the neuropeptide S receptor associated with biological processes such as appetite and food intake, movement, wakefulness, activation and anxiety [24], and the TNF receptor widely employed for the treatment of rheumatoid arthritis [25].Pyrrolo [1,2-c]imidazoles also exhibit anticancer [26,27], antioxidant, antibacterial [28], anti-inflammatory and neuroprotective [29] activities.

Results and Discussion
In this paper, we share the results concerning the synthesis of 2,3′-bipyrroles and pyrrolo[1,2-c]imidazoles via the reaction of 2-acylethynylpyrroles 1а-o with TosMIC, which is a versatile and powerful synthetic tool in heterocyclization reactions used to build five-membered heterocycles and heterofused systems [33].
At the same time, it was found that the reaction of 2-acylethynylpyrroles with Tos-MIC, depending on its conditions and substituents in the pyrrole ring, can deliver either pyrrolyl vinyl sulfones [40] or tosyl/pyrrolyl-capped 1,3-enynes [41].In the former case, the reaction proceeds under a long reflux (120 h) in the Et3N/MeCN catalytic system, whereas for the easy and rapid (reflux, 1 h) synthesis of tosyl/pyrrolyl-capped 1,3-enynes, the t-BuOK/THF system is employed.
From these results, it follows that the optimal temperature for the reaction studied is that of reflux in THF, and the search for optimal conditions for the reaction of acylethynylpyrroles with TosMIC was carried out via reflux in THF at the molar ratio of acylethynylpyrroles:TosMIC:base = 1:2:2.
To commence the reaction of 2-acylethynylpyrroles 1a-o with TosMIC, 2-benzoylethynylpyrrole (1a, 1 equiv) was refluxed with TosMIC (2 equiv) in THF in the presence of Et3N (2 equiv) for 24 h (Table 1, entry 1).However, under these conditions, not even traces of any products were found in the reaction mixture.Other organic catalysts, such as DBU (entry 2) and DABCO (entry 3), also did not promote the reaction: in all cases, the starting reagents were completely returned from the reaction.

Results and Discussion
In this paper, we share the results concerning the synthesis of 2,3 ′ -bipyrroles and pyrrolo[1,2-c]imidazoles via the reaction of 2-acylethynylpyrroles 1a-o with TosMIC, which is a versatile and powerful synthetic tool in heterocyclization reactions used to build five-membered heterocycles and heterofused systems [33].
At the same time, it was found that the reaction of 2-acylethynylpyrroles with TosMIC, depending on its conditions and substituents in the pyrrole ring, can deliver either pyrrolyl vinyl sulfones [40] or tosyl/pyrrolyl-capped 1,3-enynes [41].In the former case, the reaction proceeds under a long reflux (120 h) in the Et 3 N/MeCN catalytic system, whereas for the easy and rapid (reflux, 1 h) synthesis of tosyl/pyrrolyl-capped 1,3-enynes, the t-BuOK/THF system is employed.
From these results, it follows that the optimal temperature for the reaction studied is that of reflux in THF, and the search for optimal conditions for the reaction of acylethynylpyrroles with TosMIC was carried out via reflux in THF at the molar ratio of acylethynylpyrroles:TosMIC:base = 1:2:2.
To commence the reaction of 2-acylethynylpyrroles 1a-o with TosMIC, 2-benzoyle thynylpyrrole (1a, 1 equiv) was refluxed with TosMIC (2 equiv) in THF in the presence of Et 3 N (2 equiv) for 24 h (Table 1, entry 1).However, under these conditions, not even traces of any products were found in the reaction mixture.Other organic catalysts, such as DBU (entry 2) and DABCO (entry 3), also did not promote the reaction: in all cases, the starting reagents were completely returned from the reaction.a The reactions were carried out at a molar ratio of 1a:TosMIC:base = 1:2:2, 20 mL THF; b Isolated yield; c The reactions were carried out at a molar ratio of 1a:TosMIC:base = 1:1:1; d The reactions were carried out at a molar ratio of 1a:TosMIC:base = 1:1:0.5;e 1 eq.t-BuOH was added.
When other bases, e.g., Cs2CO3, NaOH, KOH, t-BuONa, t-BuOK (entries 5-9, 11), were employed in the reaction of TosMIC with ethynylpyrrole 1a, the complete conversion of the latter was achieved after 1 h of reflux in THF.
The highest yield of bipyrrole 2a (80%) was reached when the reaction was carried out in the presence of KOH (entry 7) or in the presence of t-BuOK (entry 11).Under these conditions, pyrroloimidazole 3а was detected only in traces.In preparative quantities, pyrroloimidazole 3a was formed only in the t-BuONa/THF system: in this case, bipyrrole 2a and pyrroloimidazole 3a were obtained in almost equal ratios ( 1 H NMR data), with their isolated yields being 27 and 37%, respectively (entry 9).
The selective formation of pyrroloimidazole 3a was observed when the reaction was carried out in the presence of NaH (molar ratio 1a:TosMIC:NaH = 1:1:1 and 1:2:2).However, in this case, the reaction was accompanied by strong tarring, and the target product was isolated in a yield of 39-45% (Table 1, entries 13,14).
As follows from the data in Table 1, the selectivity of the reaction and yields of the products depend both on the nature and ratio of bases.This can be rationalized from the points of strength of bases and their softness (hardness) according to Pearson's HSAB a The reactions were carried out at a molar ratio of 1a:TosMIC:base = 1:2:2, 20 mL THF; b Isolated yield; c The reactions were carried out at a molar ratio of 1a:TosMIC:base = 1:1:1; d The reactions were carried out at a molar ratio of 1a:TosMIC:base = 1:1:0.5;e 1 eq.t-BuOH was added.
When other bases, e.g., Cs 2 CO 3 , NaOH, KOH, t-BuONa, t-BuOK (entries 5-9, 11), were employed in the reaction of TosMIC with ethynylpyrrole 1a, the complete conversion of the latter was achieved after 1 h of reflux in THF.
The highest yield of bipyrrole 2a (80%) was reached when the reaction was carried out in the presence of KOH (entry 7) or in the presence of t-BuOK (entry 11).Under these conditions, pyrroloimidazole 3a was detected only in traces.In preparative quantities, pyrroloimidazole 3a was formed only in the t-BuONa/THF system: in this case, bipyrrole 2a and pyrroloimidazole 3a were obtained in almost equal ratios ( 1 H NMR data), with their isolated yields being 27 and 37%, respectively (entry 9).
The selective formation of pyrroloimidazole 3a was observed when the reaction was carried out in the presence of NaH (molar ratio 1a:TosMIC:NaH = 1:1:1 and 1:2:2).However, in this case, the reaction was accompanied by strong tarring, and the target product was isolated in a yield of 39-45% (Table 1, entries 13,14).
As follows from the data in Table 1, the selectivity of the reaction and yields of the products depend both on the nature and ratio of bases.This can be rationalized from the points of strength of bases and their softness (hardness) according to Pearson's HSAB principle [42,43].Indeed, in the reaction mixture, two different acids, namely CH-acid (TosMIC) and NH-acid (the pyrrole moiety), compete with each other for a base.
In the real process, the strengths of bases and their softness (hardness) as well as those of the acids depend not only on the nature of the base/alkali metal cation but also on the solvation effects, which are different for Na and K cations-i.e., the selectivity of the reaction and yields of the products are complex functions of several mutually depended variables.
Next, given the better convenience of working with KOH than with t-BuOK and its lower cost, we evaluated the substrate scope of the synthesis of bipyrroles 2a-o in the presence of KOH (Scheme 3).
principle [42,43].Indeed, in the reaction mixture, two different acids, namely CH-acid (TosMIC) and NH-acid (the pyrrole moiety), compete with each other for a base.
In the real process, the strengths of bases and their softness (hardness) as well as those of the acids depend not only on the nature of the base/alkali metal cation but also on the solvation effects, which are different for Na and K cations-i.e., the selectivity of the reaction and yields of the products are complex functions of several mutually depended variables.
Next, given the better convenience of working with KOH than with t-BuOK and its lower cost, we evaluated the substrate scope of the synthesis of bipyrroles 2a-o in the presence of KOH (Scheme 3).The experiments showed that the reaction of 2-acylethynylpyrroles 1a-o with Tos-MIC under these conditions proceeded efficiently and selectively, thus providing a short route to 2,3-dipyrroles 2a-o, which are still rare and poorly studied compounds, in good yields up to 80%.
As follows from Scheme 3, the reaction is tolerant to different acylethynylpyrroles with aliphatic and aromatic substituents in the pyrrole ring as well as 2-acylethynyl-4,5,6,7-tetrohydroindoles; i.e., the synthesis has quite a general character.
Next, a range of acylethynylpyrroles (acylethynylpyrroles 1a,b,d,h-n) were involved in the reaction with TosMIC in the t-BuONa/THF system to evaluate the scope of the novel cyclization giving hitherto unknown pyrrolo[1,2-c]imidazoles 3a-j.
Unfortunately, in contrast to the KOH/THF system, which selectively catalyzed the formation of 2,3′-bipyrroles, the t-BuONa/THF system c promoted the formation of both 2,3′-bipyrroles and pyrrolo[1,2-c]imidazoles from all the studied acylethynylpyrroles 1a,b,d,h-n (Scheme 4).The reaction products were easily separated via column chromatography (SiO2, n-hexane:diethyl ether, 5:1).The experiments showed that the reaction of 2-acylethynylpyrroles 1a-o with TosMIC under these conditions proceeded efficiently and selectively, thus providing a short route to 2,3-dipyrroles 2a-o, which are still rare and poorly studied compounds, in good yields up to 80%.
As follows from Scheme 3, the reaction is tolerant to different acylethynylpyrroles with aliphatic and aromatic substituents in the pyrrole ring as well as 2-acylethynyl-4,5,6,7tetrohydroindoles; i.e., the synthesis has quite a general character.
Next, a range of acylethynylpyrroles (acylethynylpyrroles 1a,b,d,h-n) were involved in the reaction with TosMIC in the t-BuONa/THF system to evaluate the scope of the novel cyclization giving hitherto unknown pyrrolo[1,2-c]imidazoles 3a-j.
As can be seen from Scheme 4, this reaction, like the formation of 2,3 ′ -bipyrroles, also tolerates different acylethynylpyrroles with aliphatic and aromatic substituents in the pyrrole ring as well as 2-acylethynyl-4,5,6,7-tetrohydroindoles-i.e., it also has quite a general character.
The structures of compounds 2a and 3a were proved by 1 H and 13 C NMR spectroscopy using also 2D COSY, NOESY, HMBC and HSQC techniques.The 1 H NMR spectra of 2,3 ′bipyrroles contain broad singlets of 2 NH groups at 10.23-11.77and 9.84-10.77ppm, while the spectra of pyrroloimidazole 3a show singlets of a proton at the C=N bond at 8.51-8.91 ppm and methylene group at 5.05-5.20 ppm.
Apparently, the formation of 2,3 ′ -bipyrroles 2 starts with proton abstraction from the CH 2 -group of TosMIC followed by a nucleophilic attack of carbanion A, thus generated as a C-nucleophile, on the triple bond of acylethynylpyrroles 1 to afford intermediate anion B. This anion then undergoes intramolecular cyclization with the participation of an anionic center and a carbene carbon atom to form the cyclic anion C that is further quenched by a proton of the medium.The aromatization of the intermediate bipyrrole D, as a result of the [1,3]-H shift finishes the process (Scheme 5).As can be seen from Scheme 4, this reaction, like the formation of 2,3′-bipyrroles, also tolerates different acylethynylpyrroles with aliphatic and aromatic substituents in the pyrrole ring as well as 2-acylethynyl-4,5,6,7-tetrohydroindoles-i.e., it also has quite a general character.
The structures of compounds 2a and 3a were proved by 1 H and 13 C NMR spectroscopy using also 2D COSY, NOESY, HMBC and HSQC techniques.The 1 H NMR spectra of 2,3′-bipyrroles contain broad singlets of 2 NH groups at 10.23-11.77and 9.84-10.77ppm, while the spectra of pyrroloimidazole 3a show singlets of a proton at the C=N bond at 8.51-8.91 ppm and methylene group at 5.05-5.20 ppm.
Apparently, the formation of 2,3′-bipyrroles 2 starts with proton abstraction from the CH2-group of TosMIC followed by a nucleophilic attack of carbanion A, thus generated as a C-nucleophile, on the triple bond of acylethynylpyrroles 1 to afford intermediate anion B. This anion then undergoes intramolecular cyclization with the participation of an anionic center and a carbene carbon atom to form the cyclic anion C that is further quenched by a proton of the medium.The aromatization of the intermediate bipyrrole D, as a result of the [1,3]-H shift finishes the process (Scheme 5).The assembly of pyrrolo[1,2-c]imidazoles 3 likely involves the formation of the pyrrolate anion E in the first stage due to the greater deprotonating ability of the t-BuONa/THF super-base system compared to the KOH/THF system.The anion E attacks the carbene carbon atom of TosMIC, and the forming carbanion F is neutralized with t-BuOH to give intermediate imine G.The latter undergoes intramolecular cyclization to pyrroloimidazole via the four-membered transition state H, wherein the cleavage of the N and CH2-Ts bond occurs accompanied by simultaneous C1-N and C2-CH2Ts bonding (Scheme 6).
The C, H, N microanalyses were performed on a Flash EA 1112 СHNS-O/MAS analyzer (CHN Analyzer, Thermo Fisher Scientific, Monza, Italy).Sulfur was determined via complexometric titration with Chlorasenazo III.Fluorine content was determined on a SPECOL 11 (Carl Zeiss, Jena, Germany) spectrophotometer.Clorine was determined using mercurimetric titration.The melting point (uncorrected) was determined through a Kofler micro hot-stage apparatus (Antwerpen, Belgium).High-resolution mass spectral analyses were performed on an acetonitrile solution with 0.1% HFBA on an HPLC Agilent 1200/Agilent 6210 TOF instrument equipped with an electrospray ionization (ESI) source (Agilent, USA).
All reactions were carried out in air.Acylethynylpyrroles 1a-o were prepared from corresponding pyrroles and acylbromoacetylenes in the presence of Al2O3 according to the reported procedure [13], and Tos-MIC, t-BuONa, KOH, NaH and THF were the commercial products.

General Information
IR spectra were obtained with a Vertex 70 spectrometer (Bruker, Billerica, MA, USA, 400-4000 cm -1 , films).The C, H, N microanalyses were performed on a Flash EA 1112 CHNS-O/MAS analyzer (CHN Analyzer, Thermo Fisher Scientific, Monza, Italy).Sulfur was determined via complexometric titration with Chlorasenazo III.Fluorine content was determined on a SPECOL 11 (Carl Zeiss, Jena, Germany) spectrophotometer.Clorine was determined using mercurimetric titration.The melting point (uncorrected) was determined through a Kofler micro hot-stage apparatus (Antwerpen, Belgium).High-resolution mass spectral analyses were performed on an acetonitrile solution with 0.1% HFBA on an HPLC Agilent 1200/Agilent 6210 TOF instrument equipped with an electrospray ionization (ESI) source (Agilent, Santa Clara, CA, USA).